Pharmaceutical composition with combined active agents and methods for using the same

ABSTRACT

The current invention involves a pharmaceutical composition containing a combination of two active agents. The invention also involves the use of the combination composition to the preparation of a drug combination intended to treat, control and prevent type 2 diabetes and other diseases and conditions that glucose abnormality, including abnormalities in glucose levels and glucose metabolism, is a component.

FIELD OF INVENTION

The current invention involves a pharmaceutical composition containing acombination of two active agents. The invention also involves the use ofthe combination composition to the preparation of a drug combinationintended to treat, control and prevent type 2 diabetes or other diseasesand conditions that glucose abnormality, including abnormalities inglucose levels and glucose metabolism, is a component.

BACKGROUND

Diabetes mellitus is characterized by abnormal plasma glucose level.There are more than 16 millions patients with diabetes mellitus in theUnited States. Among them, 90-95% are type 2 diabetes, which ischaracterized by insulin resistance and relative insulin deficiency. Itis a serious health problem. Health care costs related to diabetes areover $100 billions/year in the United States.

Current treatment for type 2 diabetes includes oral glucose-loweringagents and insulin. There are four major classes of oral glucoselowering agents, including biguanides (e.g., metformin), sulfonylureas(e.g., glyburide), thiazolidinediones and alpha-glucosidase inhibitors.As the recent understanding of the importance of normalizing plasmaglucose to prevent the development of diabetic complications, themagnitude of the glucose-lowering effect with monotherapy is often notsatisfactory. There has been a trend to combine agents from differentclasses to achieve better glucose control. One example is Glucovance(Bristol-Myers Squibb), which is a combination of metformin andglyburide, two commonly use oral glucose-lowering agents.

Type 2 diabetes is a complicated disease. In addition to elevated plasmaglucose concentration, other abnormalities also involve in thedevelopment of complications. Most of patients with type 2 diabetes aredyslipidemic, as characterized by high triglycerides, small dense LDL(Low Density Lipoprotein), LDL-cholesterol and low HDL (High DensityLipoprotein)-cholesterol. These abnormalities obviously contribute tothe development of cardiovascular complications. None of the currentoral glucose-lowering agents satisfactorily improve dyslipidemia, nor dothe combination of these agents. There is a need for better control ofhyperglycemia and improving dyslipidemia at the same time.

Metformin is a member of biguanides. It has been widely used in thetreatment of type 2 diabetes. It reduces elevated plasma glucoseconcentrations, mainly by suppressing hepatic glucose output. Othermembers of biguanides include phenformin and buformin.

Gemfibrozil and ciprofibrate belong to the fibrate family, a class ofagent indicated for improving lipid levels. Other fibrates includeclofibrate, fenofibrate and bezofibrate. These agents reducehypertriglyceridaemia and hypercholesterolaemia. More importantly, theirproperties on elevating HDL-cholesterol and reducing small dense LDL arehighly appreciated recently because circulating low HDL cholesterol andhigh small dense LDL are highly atherogenic in patients with type 2diabetes. Among the fibrates, some, including fenofibrate andbezafibrate, possess some degree of glucose-lowering effect (WO 99/40904and U.S. Pat. No. 5,304,575), while the others including clofibrate,gemfibrozil and ciprofibrate are lack of glucose-lowering effect(WO99/40904; Vuorinen-Markkola H et al. Diabetologia 1993, 36:161-9;Hernandez-Mijares A et al. Nutr Metab Cardiovasc Dis 2000, 10:1-6). Assuch, fibrates can be sub-divided into “glucose-lowering fibrates” and“non-glucose-lowering fibrates”. A non-glucose-lowering fibrate is afibrate that does not have statistically significant glucose loweringeffect when used alone.

The combination of a hypoglycemic agent and a lipid-improving agent hasalready been envisaged in the art, especially for treating diabeticpatients with severe hypertriglyceridaemia and hypercholesterolaemia.However, these combinations have been in the context of using respectiveagents to correct respective abnormalities, not anticipating additionalbenefits from the combinations. In fact, contradictory results wereobtained depending on the drugs used in the combination. Combination ofmetformin and members of non-glucose-lowering fibrate, such asclofibrate has failed to show better control of hyperglycemia (WO99/40904). On the other hand, combination of metformin and members ofglucose-lowering fibrate, such as fenofibrate and bezafibrate, led tobetter control of hyperglycemia (WO99/40904), although this was not asynergistic effect. It was the outcome of an additive glucose-loweringeffect of metformin and these fibrates, since synergism is defined asthe joint action of agents so that their combined effects is greaterthan the algebraic sum of their individual effects (Dorland'sIllustrated Medical Dictionary, 27^(th) Edition). From these examples,it is obvious to a person in skill of art that better hyperglycemiccontrol can be obtained when combining the use of metformin and aglucose-lowering fibrate, while better hyperglycemic control can not beobtained when combining the use of metformin and a non-glucose-loweringfibrate.

Surprisingly, the current inventor discovered that combinedadministration of metformin and gemfibrozil or ciprofibrate, two membersof the non-glucose-lowering fibrates, produced an unexpected synergisticreduction of plasma glucose concentrations.

SUMMARY OF THE INVENTION

The current invention involves a pharmaceutical composition containing acombination of two active agents. The invention also involves the use ofthe combination composition to the preparation of a drug combinationintended to treat, control and prevent type 2 diabetes or otherdiseases, conditions that glucose abnormality, including abnormalitiesin glucose level and glucose metabolism, is a component.

BRIEF DESCRIPTION OF THE TABLES

Table 1. Glucose Levels and the Metformin/Gemfibrozil Treatment.

-   Gemfibrozil alone did not have significant effect on glucose level    (P>0.05).-   * P<0.05 compared to Vehicle treated samples.-   ** p<0.05 compared to samples treated with metformin alone.    Table 2. Glucose Levels and the Metformin/Ciprofibrate Treatment.-   Ciprofibrate alone did not have significant effect on glucose levels    (P>0.05).-   * P<0.05 compared to Vehicle treated samples.-   ** p=0.0554 compared to samples treated with metformin alone.

DETAILED DESCRIPTION OF THE INVENTION

The current invention involves a pharmaceutical composition containing acombination of a biguanide, preferably metformin andnon-glucose-lowering fibrates, preferably gemfibrozil or ciprofibrate,as active agents. The invention also involves the use of a biguanide,preferably metformin and non-glucose-lowering fibrates, preferablygemfibrozil or ciprofibrate for the preparation of a drug combinationintended to treat, control and prevent type 2 diabetes or otherdiseases, conditions that glucose abnormality, including abnormalitiesin glucose level and glucose metabolism, is a component.

This invention demonstrated for the first time that the selectednon-glucose-lowering fibrates produced better control of hyperglycemicwhen combined with metformin. Furthermore, a true synergistic effect,where the effect of the combination was MORE than the sum of therespective individual agent effect, was observed with thesecombinations. This is very different from what the inventors of WO99/40904 observed, where the effect of the combination of metformin andglucose-lowering fibrates (fenofibrate or bezafibrate) was actually LESSthan the sum of the respective individual glucose-lowering effect. Inaddition, the current invention achieved a much larger magnitude ofblood glucose reduction on top of the effect of metformin alone ascompared to that of the combinations in invention of WO 99/40904 (−53.9to −65.4 vs. −30 to −31 mg/dl). This synergistic glucose-lowering effectdemonstrated that the combination of metformin and the selectednon-glucose-lowering fibrates gemfibrozil or ciprofibrate represents anovel pharmaceutical composition.

Thus, the invention involves a pharmaceutical composition consisting oftwo active agents, (1) metformin in one of its pharmaceuticallyacceptable form, and (2) a lipid-improving agent selected fromgemfibrozil and ciprofibrate in one of their pharmaceutically acceptableform, in combination with one or more pharmaceutically acceptableexcipients, such as fillers, binders, dyes, flavour enhancers and thelike as described in WO99/40904. Pharmaceutically acceptable formincludes but not limited to all pharmaceutically acceptable salts. Thecomposition contains a weight ratio of metformin or of itspharmaceutically acceptable form to gemfibrozil or of itspharmaceutically acceptable form ranges from 1:0.1 to 1:10. The weightratio of metformin or of its pharmaceutically acceptable form tociprofibrate or of its pharmaceutically acceptable form ranges from1:0.01 to 1:10.

This composition is suitable for lowering the hyperglycemia in patientswith diabetes associated with or without dyslipidemia. For thoseassociated with dyslipidemia, the dyslipidemia is effectively controlledby this composition. This composition is also expected to be suitablefor treating, controlling or preventing diseases, disorders orconditions associated with abnormal plasma glucose levels. Suchabnormalities include, but not limited to diabetes mellitus,hyperglycemia, impaired glucose-tolerance, obesity, pancreatitis andother disorders where abnormal plasma glucose level is a component.Because of the presence of lipid improving agents gemfibrozil andciprofibrate, it is further expected that the composition is suitablefor treating, controlling or preventing diseases, disorders orconditions associated with abnormal plasma lipid levels such as diabetesmellitus, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia andother diseases where abnormal plasma lipid level is a component. It isalso expected that the complications associated with diabetes anddyslipidemia, e.g., retinopathy, neuropathy, kidney failure andcardiovascular diseases, can be treated, controlled or prevented by thecomposition. The composition is suitable for administering to human andnon-human mammals.

The composition can be formulated for oral, inhalation, sublingual,buccal, intranasal, rectal, intravenous, subcutaneous, intramuscular,and transdermal administration, although other routes are not excluded.The composition is preferably administered orally in the form of gelatincapsules, effervescence tablets, coated or uncoated tablets, sachets,sugar-coated tablets, drinkable vials or solutions, microgranules orsustained-release or slow-release forms. Each dose unit contains100-1000 mg of metformin and 100-1200 mg of gemfibrozil. Alternatively,each unit can have 100-1000 mg of metformin and 20-500 mg ofciprofibrate.

EXAMPLE 1

Experiment was conducted in ob/ob mice, an animal model of diabetes.Male, 8-9 week old ob/ob mice were purchased from Jackson Laboratory(Bar Harbor, Me.) and housed in a temperature and humidity controlledroom with 12 hour light (6 am to 6 pm)/dark (6 pm-6 am) cycle and adlibitum of water and regular Purina chow. Animals were screened forplasma glucose levels and randomized into groups for experiments.

In this experiment, 8 animals were orally dosed with vehicle, metformin(90 mg/kg), gemfibrozil (100 mg/kg), or combination of metformin (90mg/kg) and gemfibrozil (100 mg/kg) once a day for 3 days. Plasma glucoseconcentrations were determined at the end of the experiment. As showedin Table 1, metformin significantly reduced plasma glucoseconcentrations while gemfibrozil alone showed minimum reduction ofplasma glucose and it was not statistically significant. When the twoagents combined, much greater magnitude of plasma glucose reduction wasobserved. The glucose reducing ability of the glucose-lowering agent(metformin) was greatly enhanced by gemfibrozil. The effect of thecombination (−153.2 mg/dl) was more than the sum of the respectiveindividual agent effect (−145.3 mg/dl). This demonstrated a synergism ofaction with the combination.

EXAMPLE 2

Experiment was conducted in ob/ob mice. The experimental condition wasthe same as Working Example 1.

In this experiment, 8 animals were orally dosed with vehicle, metformin(90 mg/kg), ciprofibrate (2.5 mg/kg), or combination of metformin (90mg/kg) and ciprofibrate (2.5 mg/kg) once a day for 4 days. Plasmaglucose concentrations were determined at the end of the experiment. Asshowed in Table 2, metformin significantly reduced plasma glucoseconcentrations while ciprofibrate showed minimum effect on reducingplasma glucose and it was not statistically significant. When the twoagents combined, much greater magnitude of plasma glucose reduction wasobserved. The glucose reducing ability of the glucose-lowering agent(metformin) was greatly enhanced by ciprofibrate. The effect of thecombination (−137.8 mg/dl) was more than the sum of the respectiveindividual agent effect (−116.3 mg/dl). This demonstrated a synergism ofaction with the combination.

TABLE 1 Glucose levels and the metformin/gemfibrozil treatment.Difference between Day 3 Vehicle & treatment Treatment (mg/dl) (mg/dl)Vehicle 406.8 ± 32.4 — Metformin 318.6 ± 29.3* −88.2 Gemfibrozil 349.7 ±39.0 −57.1 Metformin + Gemfibrozil 253.2 ± 20.9** −153.2

TABLE 2 Glucose levels and the metformin/ciprofibrate treatment.Difference between Day 4 Vehicle & treatment Treatment (mg/dl) (mg/dl)Vehicle 383.3 ± 29.0 — Metformin 299.2 ± 24.9* −84.1 Ciprofibrate 351.1± 23.1 −32.2 Metformin + Ciprofibrate 245.5 ± 19.4** −137.8

1. A method of treating a disease, disorder or condition, said methodcomprising administering to a human or non-human mammal in need thereofa pharmaceutical composition consisting of (1) metformin or apharmaceutically acceptable salt thereof, (2) a non-glucose-loweringfibrate selected from gemfibrozil or ciprofibrate, and optionally (3)one or more excipients, wherein the ratio of metformin tonon-glucose-lowering fibrate is 1:0.5 to 1:2, and wherein said disease,disorder or condition is selected from the group consisting of diabetesmellitus, hyperglycemia, impaired glucose-tolerance, insulin resistantsyndrome, obesity, and pancreatitis where abnormality in plasma glucoselevels or glucose metabolism is a component.
 2. The method according toclaim 1, wherein the administration is by means of oral, inhalation,sublingual, buccal, intranasal, rectal, intravenous, subcutaneous,intramuscular, and transdermal administration.
 3. The method of claim 1,wherein the glucose-lowering agent and the lipid-improving agent aremixed together to form an admixture and the admixture is administered tothe human or non-human mammals.